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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].
Show detailsOVERVIEW
Introduction
Revumenib is a small molecule inhibitor of menin and is used to treat children and adults with relapsed or refractory acute leukemia with a lysine methyltransferase 2A gene translocation. Revumenib is associated with mild-to-moderate elevations in serum aminotransferase levels during therapy but has not been linked to episodes of clinically apparent liver injury with jaundice.
Background
Revumenib (reh voo meh’ nib) is a small molecule inhibitor of menin and is used to treat children (above the age of 1) and adults with refractory or relapsed acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation. Menin is a chromatin adapter protein that is critical for the formation and stability of multiprotein complexes on chromatin including complexes with mutated proteins associated with leukemia, such as KMT2A and NPM1 (nucleophosmin 1). Inhibition of menin by revumenib was found to yield objective response rates in patients with various forms of relapsed or refractory acute leukemia harboring KMT2A rearrangements. In an open label, multi-cohort, multicenter study of revumenib monotherapy, a phase 1 component led to the choice of dose and enrollment criteria for a phase 2 extended treatment study, which yielded a complete response rate of 23% and an overall response rate of 63% for the 57 patients in the pivotal cohort. Based upon these results, revumenib was approved in the United States in 2024 as therapy for adults and children with relapsed or refractory acute leukemia who harbor a genetic variant such as KMT2A translocations. Revumenib is available in tablets of 25, 110 and 160 mg under the brand name Revuforj. The recommended dose regimen is based upon body weight and whether there is concomitant use of strong CYP 3A4 inhibitors; the typical dose in adults not on a CYP inhibitor is 270 mg taken orally twice daily. Therapy should be continued until unacceptable tolerance or disease progression, and optimally for at least six months. Side effects are common and can be severe. Common adverse events include hemorrhage, nausea, vomiting, musculoskeletal pain, infection, diarrhea, constipation, anorexia, edema, and fatigue. Laboratory abnormalities can include increases in serum phosphate, aminotransferases, alkaline phosphatase, and triglycerides, and decreases in neutrophils, phosphate, and potassium. Less frequent but potentially severe adverse events include differentiation syndrome, febrile neutropenia, bacterial infections, prolongation of the QTc interval, and embryo-fetal toxicity. Revumenib has a boxed warning about differentiation syndrome which can be fatal. It also has a warning against concomitant use of agents that prolong the QTc interval and recommends monitoring with EKGs before, weekly for 4 weeks, and monthly thereafter.
Hepatotoxicity
In the prelicensure trials of revumenib, a safety cohort of 94 participants who received the recommended dose was used to evaluate rates of adverse events. Fatal adverse events arose in 4 patients, 2 from differentiation syndrome, 1 from hemorrhage, and 1 from sudden death. Liver test abnormalities were frequent but usually mild-to-moderate in severity and self-limited in duration. ALT elevations arose in 37%, AST in 40%, alkaline phosphatase in 26%, and bilirubin in 11%, and ALT values were above 5 times the ULN in 4% and AST in 2%. The median time to onset of aminotransferase elevations was 21 days (range 1 to 185 days). However, there were no instances of enzyme elevations with jaundice or symptoms that were attributed to drug therapy. Since approval and clinically availability of revumenib, there have been no published case reports of clinically apparent liver injury, but clinical experience with its use has been limited.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).
Mechanism of Injury
The causes of serum enzyme elevations or liver injury during revumenib therapy are possibly due to direct toxicity of inhibition of menin facilitated pathways. Revumenib is metabolized in the liver largely via CYP 3A4 and is susceptible to drug-drug interactions with moderate or strong inducers and inhibitors of CYP 3A4. Revumenib is also a CYP 3A inducer that can alter the metabolism of concomitant agents that are CYP 3A substrates.
Outcome and Management
The product label for revumenib recommends monitoring of liver tests before and monthly during therapy. Serum aminotransferase elevations above 5 times the upper limit of normal or any elevations accompanied by jaundice or symptoms should lead to discontinuation until levels fall to less than twice ULN or an unrelated cause is found. There is little information on cross reactivity in risk for adverse events, hypersensitivity, or hepatic injury between revumenib and other kinase inhibitors used in the therapy of acute leukemia, such as ponatinib, enasidenib, and ivosidenib.
Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors
PRODUCT INFORMATION
REPRESENTATIVE TRADE NAMES
Revumenib – Revuforj®
DRUG CLASS
Antineoplastic Agents
Product labeling at DailyMed, National Library of Medicine, NIH
CHEMICAL FORMULA AND STRUCTURE
| DRUG | CAS REGISTRY NO. | MOLECULAR FORMULA | STRUCTURE |
|---|---|---|---|
| Revumenib | 2169919-21-3 | C32-H47-FN6-O4-S |
|
ANNOTATED BIBLIOGRAPHY
References updated: 7 April 2025
Abbreviations: KMT2A, lysine methyltransferase 2A; NPM1 Nucleophosmin 1; ULN, upper limit of the normal range.
- Zimmerman HJ. Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.(Review of hepatotoxicity published in 1999 before the availability of tyrosine kinase inhibitors such as revumenib).
- DeLeve LD. Erlotinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.(Review of hepatotoxicity of cancer chemotherapeutic agents discusses several tyrosine kinase inhibitors including imatinib, gefitinib, erlotinib and crizotinib, but not revumenib).
- Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.(Textbook of pharmacology and therapeutics).
- FDA. Multi-Discipline Review. 2024. https://www
.accessdata .fda.gov/drugsatfda_docs /nda/2024/218944Orig1s000TOC.cfm (FDA review of the data on efficacy and safety of revumenib submitted by the sponsor in support of its approval for therapy of refractory or relapsed acute leukemia with KMT2A rearrangements, mentions that the safety population included 135 patients with a median treatment duration of only 2.3 months, among whom there were 4 deaths, none from liver disease, and that liver test abnormalities were frequent but usually transient and mild-to-moderate in course, with ALT elevations in 37% and AST in 40%, only 2% and 4% being above 5 times ULN, and there were no cases of drug induced liver injury or concurrent rises in ALT levels and bilirubin that were attributed to drug therapy). - Spraggs CF, Xu CF, Hunt CM. Genetic characterization to improve interpretation and clinical management of hepatotoxicity caused by tyrosine kinase inhibitors. Pharmacogenomics 2013; 14: 541-54. [PubMed: 23556451](Review of genetic associations of serum ALT and bilirubin elevations during therapy with tyrosine kinase inhibitors focusing on lapatinib and pazopanib; revumenib is not discussed).
- Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf 2013; 36: 491-503. [PubMed: 23620168](Review of the hepatotoxicity of 18 tyrosine kinase inhibitors approved for use in cancer in the US as of 2013, before the availability of revumenib which is not discussed).
- Issa GC, Aldoss I, DiPersio J, Cuglievan B, Stone R, Arellano M, Thirman MJ, et al. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature. 2023; 615(7954):920-924. [PMC free article: PMC10060155] [PubMed: 36922593](Description of the mechanism of action of revumenib and role of menin in modulating cell growth proliferation and differentiation with data on a phase 1 trial in 56 patients with relapsed or refractory acute leukemia and either KMT2A or NPPM1 alterations that defined the dose-limiting toxicity [QTc prolongation] and achieved an overall response rate of 53% with adverse events including differentiation syndrome in 16% and ALT elevations in 25%, all of which resolved with discontinuation).
- Issa GC, Aldoss I, Thirman MJ, DiPersio J, Arellano M, Blachly JS, Mannis GN, et al. Menin inhibition with revumenib for KMT2A-rearranged relapsed or refractory acute leukemia (AUGMENT-101). J Clin Oncol. 2025;43:75-84. [PMC free article: PMC11687943] [PubMed: 39121437](In an open label, multicenter trial of dose-escalation followed by an expansion study using the optimal dose of revumenib in heavily pretreated patients with KMT2A rearranged acute leukemia, the modified complete response rate was 23% and overall response rate 63%, while adverse events arose in 99% of patients, led to dose reductions in 10%, discontinuations in 13%, and fatalities in 15%; and included differentiation syndrome in 18%, QTc prolongation in 26%, and aminotransferase elevations in 29%).
- Revumenib (Revuforj) for acute leukemia. Med Lett Drugs Ther. 2025;67: e8-e9. [PubMed: 39787579](Concise review of the mechanism of action, clinical efficacy, safety, and cost of revumenib shortly after its approval in the US as therapy of patients with relapsed or refractory acute leukemia with KMT2A, mentions the major adverse events including prolongation of the QTc interval and differentiation syndrome, but does not mention ALT elevations or hepatotoxicity).
- Syed YY. Revumenib: first approval. Drugs. 2025;85:577-583. [PubMed: 40072775](Review of the mechanism of action, clinical efficacy, safety, and cost of revumenib as therapy for relapsed or refractory KMT2Ar acute leukemia, mentions that revumenib monotherapy “showed an acceptable safety and tolerable profile”).
- PMCPubMed Central citations
- PubChem SubstanceRelated PubChem Substances
- PubMedLinks to PubMed
- Review Revumenib: First Approval.[Drugs. 2025]Review Revumenib: First Approval.Syed YY. Drugs. 2025 Apr; 85(4):577-583.
- Menin inhibition with revumenib for NPM1-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101 study.[Blood. 2025]Menin inhibition with revumenib for NPM1-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101 study.Arellano ML, Thirman MJ, DiPersio JF, Heiblig M, Stein EM, Schuh AC, Žučenka A, de Botton S, Grove CS, Mannis GN, et al. Blood. 2025 Aug 28; 146(9):1065-1077.
- Revumenib: a new era in acute leukemia treatment.[Trends Cancer. 2025]Revumenib: a new era in acute leukemia treatment.Martínez-Gamboa DA, Kaner J. Trends Cancer. 2025 Feb; 11(2):81-83. Epub 2025 Jan 24.
- Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia.[Int J Mol Sci. 2024]Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia.Adriaanse FRS, Schneider P, Arentsen-Peters STCJM, Fonseca AMND, Stutterheim J, Pieters R, Zwaan CM, Stam RW. Int J Mol Sci. 2024 May 30; 25(11). Epub 2024 May 30.
- Review Tovorafenib.[LiverTox: Clinical and Researc...]Review Tovorafenib.. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012
- Revumenib - LiverToxRevumenib - LiverTox
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